The novel role of IL-7 ligation to IL-7R in myeloid cells of rheumatoid arthritis and collagen induced arthritis

摘要

Although role of IL-7 and IL-7R has been implicated in the pathogenesis of Rheumatoid arthritis (RA), the majority of the studies have focused on the impact of IL-7/IL-7R in T cell development and function. Our novel data, however, document that RA patients with greater disease activity have higher levels of IL-7, IL-7R and TNF-α in RA monocytes suggesting a feedback regulation between IL-7/IL-7R and TNF-α cascades in myeloid cells which is linked to chronic disease progression. Investigations into the involved mechanism showed that IL-7 is a novel and potent chemoattractant which attracts IL-7R+ monocytes through activation of the PI3K/AKT1 and ERK pathways at similar concentrations of IL-7 detected in RA synovial fluid. To determine whether ligation of IL-7 to IL-7R is a potential target for RA treatment and to identify their mechanism of action, collagen induced arthritis (CIA) was therapeutically treated with anti-IL-7 antibody or IgG control. Anti-IL-7 antibody treatment significantly reduces CIA monocyte recruitment and osteoclast differentiation as well as potent joint monocyte chemoattractants and bone erosion markers suggesting that both direct and indirect pathways may contribute to the observed effect. We also demonstrate that reduction in joint MIP-2 levels is responsible for suppressed vascularization detected in anti-IL-7 antibody treated mice compared to the control group. In conclusion we show for the first time that expression of IL-7/IL-7R in myeloid cells is strongly correlated with RA disease activity and that ligation of IL-7 to IL-7R contributes to monocyte homing, differentiation of osteoclasts and vascularization in the CIA effector phase.